Zellweger syndrome

Disorders affecting the import pathways to mitochondria, peroxisomes, and the nucleus (e.g., mutations in the peroxisomal Pex proteins leading to Zellweger syndrome). 

Fatal hereditary disorder that typically presents in the neonatal period. Clinical features include an array of hepatic, renal and neurological dysfunctions. Patients with Zellweger syndrome rarely survive the first year of life. The disease is caused by mutations in the Pex proteins leading to an defective import of peroxisomal matrix proteins and consequently to a loss of most peroxisomal metabolic pathways. 

MOST CASES OF ZELLWEGER SYNDROME ARE DUE TO MUTATIONS IN GENES INVOLVED IN THE BIOGENESIS OF PEROXISOMES... 

Interest in import of proteins into peroxisomes has been stimulated by studies on Zellweger syndrome. This condition is apparent at birth and is characterized by profound neurologic impairment, victims often dying within a year. The number of peroxisomes can vary from being almost normal to being virtually absent in some patients. Biochemical findings include an accumulation of very long chain fatty acids, abnormalities of... 

Enzyme defects are also known to exist in the minor pathways of fatty acid degradation. In Refsum disease, the methyl-branched phytanic acid (obtained from vegetable foods) cannot be degraded by a-oxidation. In Zellweger syndrome, a peroxisomal defect means that long-chain fatty acids cannot be degraded. 

Zellweger syndrome Is a llpid storage disorder caused by impaired peroxisome biogenesis due to deficiency or functional defect of one of eleven proteins involved in the complex mechanism of peroxisomal matrix protein import and assembly of the organelle. 

The essential amino acid lysine (2,5-diaminohexanoic acid) can be degraded via two pathways, viz. the so-called saccharopine pathway and the pipecolic acid (PA) pathway. Both pathways merge at the level of a-aminoadipic acid semialdehyde (AASA). It is generally accepted that the saccharopine pathway constitutes the major breakdown pathway. However, the PA pathway has attracted much attention since the discovery of the association between the presence of elevated PA levels and Zellweger syndrome almost 40 years ago. Mainly because the analysis of amino acids was the primary biochemical approach for studying presumed inborn errors of metabolism, PA in Zellweger syndrome was discovered even before it was realized that this disorder was based on a defect of peroxisomal functions. 

Generalized peroxisomal dysfunction (Zellweger syndrome and variants). 

PA reference values for plasma, urine, and CSF are 2.511.25 pmol/1, 0-6 mmol/ mol creatinine, and <0.12 pmol/1, respectively. Pathological values may cover a very wide range as an example, patients with the Zellweger syndrome may have plasma PA levels up to 170 pmol/1 the CSF of a AASA-dehydrogenase-deficient patient may show PA levels as high as 3 pmol/1. 

To date there are no true inborn errors associated with essential fatty acid metabolism. However, we do know that the final step of DHA formation is the peroxisomal beta-oxidation of a homologous C24 fatty acid [7]. Consequently, patients with a generalised defect of peroxisomal function, such as Zellweger syndrome, are prone to develop deficiencies of essential fatty acids including DHA [9]. 

Patients with a peroxisome biogenesis defect (Zellweger syndrome) are especially low in DHA for two reasons (1) they have no peroxisomal fatty acid /1-oxidation and... 

Wilson GN, Holmes RD, Custer J, Lipowitz JL, Stover J, Datta N, Hajra A (1986) Zellweger syndrome diagnostic assays, syndrome delineation and potential therapy. Am J Med Genet 24 69-82... 

Peroxisomal disorders (Zellweger syndrome, Refsum s disease, neonatal adre-noleukodystrophy) are characterised by defective peroxisome biogenesis, or, being present, peroxisomes lacking / -oxidative enzymes. In the BA biosynthetic pathway, dihydroxycoprostanic acid (DHCA) and trihydroxycoprostanic acid (THCA) are /1-oxidised in peroxisomes to produce CA and CDCA, respectively, whereas peroxisomal disorders cause a defective oxidation of the BA precursor side chain, which leads to an accumulation of C27 bile acids, notably 3 ,7 -dihydroxy-5/3-cholesta-noic acid (DHCA) and 3a,7a,12a-trihydroxy-5/l-cholestanoic acid (THCA), in the plasma and urine of affected patients. 

A second important difference between mitochondrial and peroxisomal fi oxidation in mammals is in the specificity for fatty acyl-CoAs the peroxisomal system is much more active on very-long-chain fatty acids such as hexacosanoic acid (26 0) and on branched-chain fatty acids such as phytanic acid and pristanic acid (see Fig. 17-17). These less-common fatty acids are obtained in the diet from dairy products, the fat of ruminant animals, meat, and fish. Their catabolism in the peroxisome involves several auxiliary enzymes unique to this organelle. The inability to oxidize these compounds is responsible for several serious human diseases. Individuals with Zellweger syndrome are unable to make peroxisomes and therefore lack all the metabolism unique to that organelle. In X-linked adrenoleukodystrophy (XALD), peroxisomes fail to... 

Several genetic diseases involve the development of peroxisomes.14/35/58/59 Most serious is the Zellweger syndrome in which there are no functional peroxisomes. Only "ghosts" of peroxisomes are present and they fail to take up proteins containing the C-terminal peroxisome-targeting sequence SKL.60/60a There are many symptoms and death occurs within the first year. Less serious disorders include the presence of catalaseless peroxisomes.603... 

The elevation of VLCFA can be detected in most body tissues and fluids and forms the basis for a diagnostic assay for the identification of affected individuals.The most frequently used test is the measurement of VLCFA in plasma which has been shown to be very sensitive. Although VLCFA are increased in some of the other peroxisomal disorders, including Zellweger syndrome, infantile Refsum disease, and neonatal ALD, the clinical presentations of these disorders are very different from X-ALD, and the discrimination of... 

Cholesterol and phospholipids. Most lipids found in myelin are common to other cellular membranes. Cholesterol content is high and cholesterol esters are not present in normal myelin. Phospholipids are also common to other cellular membranes, except for the great quantity of ethanolamine phosphoglycerides in the plasmalogen form. The synthesis of plasmalogens is modified in Zellweger syndrome which is a peroxisomal syndrome that also increases VLCFA. This syndrome and other peroxisomal diseases may cause demyelination (Powers, 2005). 

Zellweger syndrome, which results from the absence of functional peroxisomes, is characterized by liver, kidney, and muscle abnormalities and usually results in death by age six. The syndrome is caused by a defect in the import of enzymes into the peroxisomes. Here we see a pathological condition resulting from an inappropriate cellular distribution of enzymes. 

Lazarow, RB., Black, V., Shlo, H., Fujlkl, Y., Hajra, A.K., Datta, N.S., Bangaru, B.S., Dancls, J. Zellweger syndrome biochemical and morphological studies on two patients treated with clofibrate. Pediatr. Res. 1985 19 1356-1364... 

Maeda, K., Kimura, A., Yamato, Y., Nittono, H., Take , H., Sato, T., Mitsubuchi, H., Mural, T., Kurosawa, T. Oral bile acid treatment in two Japanese patients with Zellweger syndrome. J. Pediatr. Gastroenterol. Nutr. 2002 35 227-230... 

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